tbuckley/cabot-search huggingface dataset:
Immunomodulatory response to neoadjuvant nivolumab in non-metastatic clear cell renal cell carcinoma.
Authors: Nirmish Singla, Thomas Nirschl, Aleksandar Obradovic, Eugene Shenderov, Kara A. Lombardo, Xiaopu Liu, Alice Pons, Jelani Zarif, Steven P. Rowe, Bruce J. Trock, Hans J. Hammers, Trinity Bivalacqua, Phillip Pierorazio, Julie S. Deutsch, Tamara L. Lotan, Janis M. Taube, Yasser Ged, Michael A. Gorin, Mohamad E. Allaf, Charles G. Drake
Journal: Journal of Clinical Oncology (2023)

708 Background: Novel perioperative strategies are needed to reduce recurrence rates in patients undergoing nephrectomy for high-risk, non-metastatic clear cell renal cell carcinoma (ccRCC). We sought to (1) elucidate the effects of PD-1 inhibition on primary tumor-infiltrating and circulating immune cell populations in ccRCC and (2) correlate tumor microenvironment and circulating immune cell compositions with response to anti-PD-1 therapy. Methods: We conducted a prospective, phase I trial of neoadjuvant nivolumab prior to nephrectomy in 15 evaluable patients with non-metastatic ccRCC. We leveraged tissue from this cohort to elucidate the effects of PD-1 inhibition on immune cell populations in ccRCC and correlate the evolving immune milieu with anti-PD-1 response using fluorescence-activated cell sorting, bulk RNA sequencing with protein activity inference, and enzyme-linked immunosorbent assay for circulating cytokines. Results: We found that nivolumab durably promotes a pro-inflammatory state within the primary tumor, as evidenced by a sustained increase in the effector T cell phenotype and decreased representation of regulatory T cell subsets. Baseline immune infiltration within the primary tumor including T effector and myeloid enrichment along with angiogenic depletion correlates with nivolumab responsiveness. Nivolumab increases CTLA-4 expression in the primary tumor, and subsequent nephrectomy increases circulating concentrations of sPD-L1, sPD-L3 (sB7-H3), and s4-1BB. Conclusions: Our findings form the basis to consider neoadjuvant immune checkpoint inhibition (ICI) for high-risk ccRCC while the tumor remains in situ and provide the rationale for perioperative strategies of novel ICI combinations. Clinical trial information: NCT02575222 .
Chemotherapy, immunotherapy, or combination first-line treatment for metastatic urothelial carcinoma of the bladder: A large real-world experience.
Authors: Sanjana Ranganathan, Carlos Riveros, Jiaqiong Xu, Michael Geng, Emily Huang, Maryam Anis, Taliah Muhammad, Jun Zhang, Eleni Efstathiou, Christopher J.D. Wallis, Guru P. Sonpavde, Raj Satkunasivam
Journal: Journal of Clinical Oncology (2023)

477 Background: First-line therapy for metastatic urothelial carcinoma of the bladder (mUC) consists of platinum-based chemotherapy in most patients and PD1/L1 inhibitors in selected patients. Multiple combination chemo-immunotherapy trials failed to show a clear benefit over chemotherapy alone. We sought to use real-world data to evaluate clinical and sociodemographic factors associated with receipt of first-line chemotherapy, immunotherapy or combination chemo-immunotherapy treatment for metastatic bladder cancer and examined differences in overall survival (OS). Methods: We used the National Cancer Database to identify patients with stage IV UCB diagnosed between 2014 and 2018, who were treated with first-line immunotherapy, chemotherapy, or combination treatment. We performed multivariable logistic regression modeling to determine factors associated with treatment receipt. An extension of inverse probability treatment weighting (IPTW) obtained from multinomial logistic regression was used to balance clinical and sociodemographic differences between treatment groups. Adjusted Kaplan-Meier survival analysis and multivariable Cox proportional hazards regression were used to evaluate the association between treatment and OS. Results: A total of 4,169 patients were identified in the cohort; 3,255 (78.1%) were treated with chemotherapy, 601 (14.4%) with immunotherapy, and 313 (7.5%) with combination treatment. Multivariable analysis identified increasing age (RRR: 1.07, 95% CI, 1.06-1.08), comorbidity burden (Charlson-Deyo 2, RRR: 1.65, 95% CI, 1.21-2.24 and Charlson-Deyo 3, RRR: 2.11; 95% CI, 1.51-2.93), and treatment at an academic facility (RRR: 1.26; 95% CI, 1.03-1.53) as independent predictors of receiving immunotherapy. Treatment at an academic facility (RRR: 1.29, 95% CI, 1.01-1.65) was associated with receipt of combination treatment. After IPTW, we found that combination therapy (hazard ratio [HR]: 0.72; 95% CI, 0.62-0.83), but not immunotherapy alone, was associated with improved survival compared to chemotherapy. These data are limited by inability to determine platinum eligibility, and residual confounding. Conclusions: Patients with older age and more comorbidities were more likely to receive immunotherapy than chemotherapy for first-line treatment of metastatic urothelial carcinoma of the bladder. Modest real-world utilization of chemo-immunotherapy was observed to be higher in academic centers and was associated with improved survival compared to chemotherapy. The study is limited by retrospective design; prospective data are necessary to identify patients who may benefit from combination chemo-immunotherapy.
Treatment-free survival (TFS) outcomes from the phase II study of nivolumab and salvage nivolumab + ipilimumab in advanced clear cell renal cell carcinoma (aRCC) (HCRN GU16-260-Cohort A).
Authors: Michael B. Atkins, Opeyemi Jegede, David F. McDermott, Naomi B. Haas, Mehmet Asim Bilen, Mark N. Stein, Jeffrey A. Sosman, Elizabeth R. Plimack, Robert S. Alter, Moshe Chaim Ornstein, Michael E. Hurwitz, David J. Peace, David Johnson Einstein, Paul J. Catalano, Hans J. Hammers, Meredith M. Regan
Journal: Journal of Clinical Oncology (2023)

604 Background: Treatment with immunotherapy can be associated with prolonged disease control after discontinuation without the need for further anticancer therapy. Toxicity from therapy can also persist after cessation. TFS with and without toxicity can characterize survival time. Significant TFS was reported for CheckMate 067 trial in pts with metastatic melanoma (Regan et al JITC 2021) and CheckMate 214 trial for pts with aRCC (Regan et al CCR 2021), but treatment was often halted for toxicity rather than a pre-defined treatment endpoint. We therefore sought to assess TFS in the HCRN GU16 260 trial, which was designed to reduce toxicity and to cap immunotherapy duration (Atkins et al JCO 2022). Methods: Data were analyzed from 128 patients (pts) with clear-cell aRCC treated with first-line nivolumab (NIVO) monotherapy for up to 2 years. As part of the protocol, salvage nivolumab/ipilimumab (NIVO/IPI) for up to 1 year was provided to eligible patients with disease progression at any point or stable disease at 48 weeks (28% of pts). TFS was defined as the area between Kaplan-Meier curves for time from registration to protocol therapy cessation and for time from registration to subsequent therapy initiation or death, estimated from 36-month (mo) mean times. The time on treatment or off treatment with grade 3+ treatment-related adverse events (TRAEs) was also captured. Results: At 36 mos from enrollment, 68.3% of pts were alive: 96.8% of IMDC favorable-risk (FAV) pts and 56.6% of those with intermediate/poor-risk (I/P), respectively. The 36-mo mean time on protocol therapy was 11.5 mos (16.0 mos for FAV pts and 9.6 mos for I/P pts). The 36-mo mean TFS for the whole population was 9.4 mos. For FAV pts the mean TFS was 12.9 mos, of which TFS with grade 3+ TRAEs was 1.5 mos. For I/P pts, the mean TFS was 8.0 mos, of which TFS with grade 3+ TRAEs was 1.0 mos. At 36 mos, 65.6% of FAV pts and 27.1% of I/P pts were alive and second-line treatment-free. Conclusions: NIVO monotherapy with salvage NIVO/IPI in non-responders is an active treatment approach in treatment-naïve pts with aRCC and results in substantial TFS and toxicity-free TFS. TFS was particularly noted in pts with FAV disease, further supporting the use of an immunotherapy-only regimen in this population. Clinical trial information: NCT03117309 . [Table: see text]
Real-world clinical outcomes of patients with localized prostate cancer (LPC) treated with external beam radiation therapy (EBRT).
Authors: Lawrence Ivan Karsh, Shawn Du, Jinghua He, Dexter Waters, Erik Muser, Neal D. Shore
Journal: Journal of Clinical Oncology (2023)

330 Background: Patients (pts) with localized prostate cancer (LPC) or locally advanced prostate cancer (PC) have several treatment options, including external beam radiation therapy (EBRT) and radical prostatectomy, which can be curative in some pts. However, limited real-world evidence exists on the long-term clinical outcomes of these pts, particularly those with high-risk LPC (HRLPC). This study examines real-world clinical outcomes for HRLPC and low/intermediate risk LPC (LIRLPC) pts treated with EBRT in the US. Methods: A retrospective study using Surveillance, Epidemiology, and End Results (SEER)-Medicare linked registry-claims data from 2012−2019 included LPC pts aged ≥65 treated with EBRT as initial definitive therapy. Baseline demographic and clinical characteristics were summarized for HRLPC and LIRLPC pts. Clinical outcomes of interest (overall survival, metastasis-free survival [MFS] and time to initiation of advanced PC treatment) were compared using Kaplan-Meier (KM) and Cox proportional hazards (PH) models. Results: Of 11,127 LPC pts treated with EBRT within 6 months of LPC diagnosis, ~40% (n=4,414) were HRLPC and ~60% (N=6,713) were LIRLPC. Patient characteristics for both groups appeared similar, with mean age at EBRT initiation &gt;70 years, 86% white, and mean follow-up time &gt;40 months. ADT was used with EBRT in 78% HRLPC and 34% LIRLPC. Median (IQR) duration of ADT therapy (via KM analysis) was 9.9 (5.8, 21.5) months for HRLPC and 7.2 (5.3, 9.8) months for LIRLPC. A higher proportion of HRLPC vs LIRLPC pts experienced metastasis, death, and progression to advanced PC therapies (medians were not reached). Unadjusted Cox PH survival analyses showed higher risk of mortality, metastasis, and advanced PC therapy use for HRLPC vs LIRLPC pts. Conclusions: This real-world study of clinical outcomes in pts with HRLPC and LIRLPC treated with EBRT suggested substantial additional disease burden in pts with HRLPC and highlights the need for additional strategies and treatments to improve clinical outcomes in pts with HRLPC. [Table: see text]
Early efficacy results from atezolizumab (ATZ) with split doses of cisplatin plus gemcitabine in patients with locally advanced or metastatic urothelial carcinoma (SOGUG-AUREA).
Authors: Guillermo de Velasco, Iciar García-Carbonero, Emilio Esteban-Gonzalez, Alvaro Pinto, David Lorente, Alfonso Gomez De Liano Lista, Esther Martínez Ortega, Laura Jimenez Colomo, Javier Puente, Iria Gonzalez, Ovidio Fernandez-Calvo, Georgia Anguera
Journal: Journal of Clinical Oncology (2023)

502 Background: Urothelial carcinoma (UC) commonly affects patients (pts) who are ineligible for full doses of cisplatin-based chemotherapy (CT) due to bad performance status, advanced age, or renal impairment. The combination of split-dose cisplatin with ATZ might be a feasible treatment for pts with UC who are unfit for full doses of cisplatin. Methods: The phase II SOGUG-AUREA clinical trial recruited treatment-naive pts in advanced or metastatic settings considered unfit for full dose of platinum-based CT. Pts received a split dose of cisplatin (35 mg/m2) and gemcitabine (1000 mg/m2) days 1 and 8 (up to 6 cycles) in combination with 3-weekly ATZ 1200 mg in D1 intravenously until progression, unacceptable toxicity, or absence of clinical benefit. Here we present the early results from the confirmed objective response rate (ORR) according to RECIST 1.1, the primary endpoint for efficacy, progression-free survival (PFS), overall survival (OS) and safety. Results: Between Jan 2021 and Mar 2022, 82 pts were screened, 66 pts were enrolled and received at least one dose of study treatment. Baseline characteristics are outlined in the table. The median duration of ATZ treatment was 4.4 months (m) (95%CI: 4.1-4.6). The confirmed ORR was 40.9%, with 5 (7.6%) pts having CR and 22 (33.3%) PR. The median duration of the response was 7 m (95%CI: 4.9-10.4). The clinical benefit rate (CBR) was 53%, and SD (maintained &gt; 6m) was reported in 8 (12.1%) pts. Eight (12.1%) pts were not evaluable for response due to exitus previous to disease evaluation (9.1%), non measurable target lesions (1.5%) or withdrawal (1.5%). With a median follow-up of 9.3 m (range: 0.6-18.1), the median PFS was 6.9 m (95%CI: 6.4-9.2), with a 6-m PFS rate of 67.1% (95% CI: 56.5-79.7). The reasons for platinum ineligibility did not correlate with PFS. The 6-m OS rate was 78.2% (95%CI: 68.6-89). Most frequent grade 3-4 toxicities were neutrophil count decreased (24.2%), anemia (21.5%) and platelet count decreased (13.6%). Conclusions: ATZ with split doses of CT was safely administered in a population of frail pts with mUC who were unfit for CT showing promising preliminary survival outcomes in terms of response. Final survival results are awaited. Clinical trial information: NCT04602078 . [Table: see text]
Evolution of systemic therapy from 2015 to 2019 for older patients in the United States with metastatic renal cell carcinoma.
Authors: Ryan Dz-Wei Chow, Jessica B. Long, Sirad Hassan, Stephanie B. Wheeler, Lisa Spees, Michael Leapman, Michael E. Hurwitz, Hannah Dzimitrowicz McManus, Cary Philip Gross, Michaela Ann Dinan
Journal: Journal of Clinical Oncology (2023)

610 Background: Immune checkpoint inhibitors (IOs) and oral anti-cancer agents (OAAs) have demonstrated survival improvements in randomized trials of patients with metastatic renal cell carcinoma (mRCC). IOs were approved as second-line mRCC therapy in 2015 (nivolumab), followed by first-line approval in 2018 (ipilimumab/nivolumab). Real-world changes in overall treatment rates and IO usage have not been examined in patients over 65, who are often underrepresented in trials. Disparities in mRCC outcomes have persisted in the era of these novel therapies, raising the question of whether receipt of IOs and OAAs varies by race and ethnicity. Methods: We conducted a retrospective cohort study of Medicare beneficiaries over age 65 diagnosed with mRCC from 2015 through 2019 who were enrolled in fee-for-service Medicare Parts A, B, and D from 1 year prior to diagnosis through 1 year after presumed diagnosis or until death. We identified our cohort using diagnosis codes for primary or secondary kidney malignancy. We queried claims from 2014-2020, identifying receipt of IO, OAA, or other systemic therapies in the 2 months before through 1 year after diagnosis. Patients that received both IOs and OAAs were categorized as IO if both therapies were started within 60 days; otherwise, patients were categorized by the first therapy received. We assessed trends in treatment from 2015-2019, stratifying by race and ethnicity to compare non-Hispanic White (NHW) patients with Hispanic, Black, Asian, Pacific Islander, American Indian, Native Alaskan, or Other patients (grouped as non-NHW due to limited sample sizes). Results: We identified 15,407 patients who were diagnosed with mRCC between 2015-2019 and met study criteria. Non-Hispanic White patients comprised 84% of our sample. Receipt of IOs increased from 4% of patients in 2015 to 37% in 2019 ( P &lt; .001). Among NHW patients, IO treatment receipt increased from 4% in 2015 to 38% in 2019 ( P &lt; .001); for non-NHW patients, IO receipt grew from 3% in 2015 to 31% in 2019 ( P &lt; .001). OAA usage decreased over time, from 31% of all patients in 2015 to 11% in 2019 ( P &lt; .001). The percent of NHW patients treated with any systemic therapy increased from 51% in 2015 to 60% in 2019 ( P &lt; .001), while there was no significant change for non-NHW patients (51% in 2015 to 54% in 2019; P = 0.27). Conclusions: Among Medicare beneficiaries, receipt of IO therapy for mRCC increased from 2015-2019. Receipt of any systemic therapy significantly increased over time for NHW patients, but not for non-NHW patients. [Table: see text]
Patterns of failure with <sup>18</sup>F-DCFPyL PSMA PET/CT in the post-prostatectomy setting: A regional cohort analysis.
Authors: Samantha S. Sigurdson, Khalid al Salman, Aruz Mesci, Theodoros Tsakiridis, Ian S. Dayes, Kimmen Quan, Mira Goldberg, Kara Schnarr, Anil Kapoor, Bobby Shayegan, Glenn Bauman, Katherine Zukotynski, Himu Lukka
Journal: Journal of Clinical Oncology (2023)

309 Background: The participants are patients enrolled in the PSMA-PET Registry for Recurrent Prostate Cancer (PREP) who were referred for [18F]-DCFPyL PET/CT at our institution in Hamilton, Canada. The Registry is the only funded access to PSMA PET/CT for patients in Ontario. Methods: Our analysis includes all men who had a PSMA PET/CT on the Registry between April 2019 and December 2021 and are either node positive, or persistently detectable PSA after initial radical prostatectomy (RP), or biochemical failure after initial RP. Results: In total 177 men were enrolled on the Registry who met the above criteria. 170 men had complete pathological information available and were included. The pre-PSMA PET/CT median PSA was 0.27 ng/mL. Overall, the probability of a positive PSMA PET/CT result was 59.4%, and the incidence increased with increasing PSA. Lymph node (LN) and distant metastases (DM) were detected more frequently in patients with Grade groups 3-5 and higher pathologic tumor (pT) and nodal (pN1) disease. Across all 170 patients the most common site for LN recurrence was in the internal iliac chain (15.9%), followed by the external iliac (14.7%), obturator (11.8%), common iliac (10.0%), pre-sacral (8.8%), para-aortic (7.7%), and peri-rectal (5.9%) chains. The PSMA PET/CT recurrence rate, PSA, and pathological tumor stage is reported, with the location of the recurrence indicated. Conclusions: Our prospective study elucidates patterns of failure for prostate cancer patients with biochemical recurrence after RP and could impact management at diagnosis and after RP. There is a significant risk of pelvic LN positivity on PSMA PET/CT, which emphasizes the importance of including pelvic LNs within salvage radiation volumes. [Table: see text]
C-reactive protein (CRP) as a predictive marker for outcomes with avelumab + axitinib (A + Ax) in patients with poor-risk advanced renal cell carcinoma (aRCC): Exploratory analysis from JAVELIN Renal 101.
Authors: Yoshihiko Tomita, Robert J. Motzer, Toni K. Choueiri, Brian I. Rini, Hirotsugu Uemura, Mototsugu Oya, Laurence Albiges, Yosuke Fujii, Yoshiko Umeyama, Bo Huang, Alessandra Di Pietro, Manuela Schmidinger
Journal: Journal of Clinical Oncology (2023)

670 Background: Analyses from the phase 3 JAVELIN Renal 101 trial (NCT02684006) suggested that CRP levels at baseline (BL) and early after treatment may predict outcomes with A + Ax in patients with aRCC. In addition, many patients with International Metastatic RCC Database Consortium (IMDC) poor risk who had prolonged progression-free survival (PFS) and overall survival (OS) were observed at the third interim analysis of OS. We analyzed the association between CRP levels and prolonged PFS/OS with A + Ax in patients with IMDC poor risk. Methods: CRP levels were assessed at screening and on day 1 of each 6-week cycle. Patients in the A + Ax arm with 3 or 4-6 IMDC risk factors were categorized into subgroups with CRP normal (BL CRP &lt;10 mg/L), normalized (BL CRP ≥10 mg/L and ≥1 CRP value decreased to &lt;10 mg/L during 6-week treatment), or non-normalized (CRP ≥10 mg/L at BL and during 6-week treatment). CRP levels were compared in patients with prolonged PFS/OS (PFS ≥24 months [mo] and OS ≥30 mo) or PFS &lt;24 mo (any OS duration). Results: In the A + Ax arm (N=442), 44 and 29 patients had 3 or 4-6 IMDC risk factors, of whom 7 and 5 had prolonged PFS/OS, and 26 and 20 had PFS &lt;24 mo, respectively (Table). Most patients with 3 or 4-6 risk factors with prolonged PFS/OS were in the normal or non-normalized CRP group, respectively. In patients with 3 risk factors with prolonged PFS/OS, CRP levels were generally low at BL and remained low for 24 mo. In patients with 4-6 risk factors with prolonged PFS/OS, CRP levels were high at BL and decreased markedly within 6 weeks, then maintained for 24 mo. Conclusions: In patients with poor-risk aRCC treated with A + Ax, a low CRP level at BL and during treatment or a rapid decrease in high CRP levels might predict favorable long-term outcomes, although CRP levels are unspecific and may increase/decrease with other diseases/comorbidities. Clinical trial information: NCT02684006 . [Table: see text]
Does body mass index matter in predicting renal mass sizes? Comparison of imaging modalities.
Authors: Young Son, Benjamin Fink, Brian Thomas, Dayna DeVincentz, Raeann Dalton, Thomas Mueller, Gordon Andrew Brown
Journal: Journal of Clinical Oncology (2023)

619 Background: Renal cell carcinoma is most commonly diagnosed as an incidental mass detected on cross sectional imaging. When a renal mass is thought to be cancerous, size on imaging is important for clinical decision-making, as there is a known positive correlation with increasing size prognostic outcomes. Image quality may be adversely impacted by a variety of factors, and we sought to assess the impact of body mass index (BMI) on the ability to obtain accurate renal mass sizes across multiple imaging modalities. Methods: A retrospective multi-institutional chart review was performed for adult patients undergoing partial or radical nephrectomy between January 2018 and December 2021 from three different hospitals and six operating surgeons. BMI groups were assigned by BMI 1: &lt;18.5, BMI 2: 18.5-24.9, BMI 3: 25-29.9, BMI 4: 30-34.9, and BMI 5: &gt;35. Differences between greatest dimensions were compared between pathological measurement and each imaging modality: computerized tomography (CT) with and without contrast, ultrasound (US), and magnetic resonance imaging (MRI). Paired t test was used to analyze the total cohort mean difference testing for a difference between modalities and pathology report. T-tests and Wilcoxon signed-rank tests were used to compare the different BMI groups. Results: A total of 234 patients met inclusion criteria and were identified by age, gender, procedure, and renal mass location. There was a statistically significant difference between the greatest dimension as measured on CT with contrast and MRI compared to pathological measurement in the total cohort. Sub analysis of BMI groups showed the differences in size in BMI group 4 (mean (SD)) (0.46 cm (0.52)) and BMI group 5 (0.4 cm (0.51)) were found to have a significant difference in size estimates compared to BMI 3 for CT with contrast (Table). There was no difference for size estimates by BMI group for any other imaging modality. Conclusions: While CT with contrast and MRI are important modalities for their tissue enhancement abilities, they may not be the strongest choice for strict renal mass size estimation. Specifically, CT with contrast becomes less accurate at estimating mass size for patients with BMI &gt;30. [Table: see text]